Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.790215
Title: An investigation into the drug crystallisation phenomenon in the skin
Author: Goh, C. F.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Abstract:
The stratum corneum (SC) is the outermost skin layer and limits the penetration of most of drugs. Percutaneous absorption of drug is limited by not only the skin barrier itself, but also the thermodynamic of a formulation. For many formulations such as gels, creams and lotions, drug permeation usually slows down over time and drug is deposited in and on the skin. Therefore, drug crystallisation has been proposed as a possible contribution to poor bioavailability of the topical formulations. The main objective of this thesis is to investigate the drug crystallisation phenomenon occurring in the skin following application of various saturated drug solutions. Characterisation of drug crystal formation in the skin was performed using different techniques including thermal analysis, spectroscopic and microscopic approaches and X-ray diffraction (XRD) analysis. Firstly, the thermal behaviour of drug crystals attached on tape strips was evaluated at the nano scale using transition temperature microscopy (TTM), a type of localised nano-thermal analysis. The presence of drug crystals was determined by examining the transition temperature and its related thermal events on the microscopic images, namely the drug melting event. These findings point to possible evidence for drug crystallisation in vitro in the inter-corneocyte space of the SC via formation of nanocrystals at a depth of 4 - 7 µm. Following on from this, bulk thermal analysis using differential scanning calorimetry was applied to study the effect of penetration enhancers and drug on the thermal transitions of porcine SC. Analysis of the modification of the thermal transitions was carried out to evaluate any possible implications of drug crystallisation on the thermal behaviour of the SC. However, no major effect on the skin thermal transitions was reported for the presence of drug. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy was selected as a spectroscopic approach to examine drug crystallisation ex vivo. This technique was complemented by spectral data deconvolution using multivariate data analysis and microscopic observations. Drug in the crystalline form was shown in the series of ATR-FTIR spectra collected from the tape stripped skin samples up to the first two tape strips (0.7 - 1.3 µm). Finally, drug distribution and crystallisation in the skin was investigated using confocal Raman spectroscopy and XRD analysis which was carried out at a synchrotron station. The detection of skin components (collagen fibres) and drug crystals was recorded in different XRD profiles due to the difference in the arrangement of structural units of the samples. The XRD analysis detected drug crystals in deeper layers of the skin (20 - 25 µm) in contrast to TTM and ATR-FTIR spectroscopy. This was probably limited by the number of tape strip and the detection limit of the instruments. To conclude, this thesis detailed the detection of drug crystals in the SC in vitro and ex vivo as a function of depth, varying from ~1 µm to 25 µm into the skin. Different techniques reported different depth profiles for drug crystallisation in the skin in vitro. Further in vivo validation using other biophysical approaches is necessary for a complete understanding of drug crystallisation.
Supervisor: Lane, M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.790215  DOI: Not available
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